Mineralocorticoidal 3-ethers

ABSTRACT

AS STEROIUS EXHIBITING STRONG MINERALOCOTICOIDAL ACTIVITIES AND WEAK GLUCOCORTICOIDAL ACTIVITIES, ARE COMPOUNDS OF THE FORMULA:   3-R1-O-,4-R2-,5-R3-,21-R4-PREGNAN-20-ONE   WHEREIN R1 IS LOWER ALKYL OR CYCLO ALKYL; R2 AND R3 REPRESENT HYDROGEN OR TOGETHER A DOUBLE BOND; AND R4 IS A FREE OR ESTERIFIED HYDROXY GROUP.

United States Patent Office 3,597,453 Patented Aug. 3, 1971 US. Cl.260397.47 7 Claims ABSTRACT OF THE DKSCLOSURE As steroids exhibitingstrong m ineralocorticoidal activities and Weak glucocorticoidalactivities, are compounds of the formula:

wherein R is lower alkyl or cyclo alkyl;

R and R represent hydrogen or together a double bond;

and

R is a free or esterified hydroxy group,

BACKGROUND OF THE INVENTION This invention relates to steroids, and inparticular to those exhibiting mineralocorticoidal activity.

It is known that the natural mineralocorticoids, such asdesoxycorticosterone and aldosterone, are orally inactive. There are,however, certain synthetic corticosteroids, such as9a-fiuorohydrocortisone and derivatives thereof, which are orally activemineralocorticoidal agents, but they also exhibit deleteriously strongglucocorticoid side eiiects. Accordingly, these known orally activesynthetics must be administered with caution and only to certainpatients.

SUMMARY OF THE INVENTION An object of this invention is to providesteroids having a high index of mineralocorticoidal to glucocorticoidalactivities.

Another object is to provide novel steroids, processes for theirpreparation, and intermediates for such processes.

Other objects include pharmaceutical compositions and methods ofadministration for effecting mineralocorticoidal activities.

Upon further study of the specification and claims, other objects andadvantages of the present invention will become apparent.

To attain the objects of this invention, there are pro vided compoundsof Formula I, as follows:

C.7H R C 0 '5 R10 NW IIt Rs 2 (I) wherein R is lower alkyl orcycloalkyl;

R and R represent hydrogen or together a double bond;

and

R represents a free or esterified hydroxy group, as well as ester saltsof the acidic or basic 21-esters thereof.

These compounds exhibit, upon oral administration, highmineralocorticoidal activities without the occurrence of appreciableglucocorticoid side effects. Thus, for example, 306methoxy-Zl-hydroxy-4-pregnen-20=one possesses a sodium-retaining anddiuresis-inhibiting activity approximating that of 9ocfill0i0h1YdI'OCOI'liiS0l'16, but without effecting a thymus involution.

Consequently, the compounds of Formula I are valuable drugs, and, inparticular, can be administered to animals without danger for combatingAddisons disease and hypotonia.

In addition to the aforementioned activities, the compounds exhibit ablood pressure elevating activity.

It is also to be noted that the compounds of Formula I are suitable asintermediates for the preparation of other pharmacologically effectivecompounds.

For example, by ether cleavage and subsequent oxidation, followed byesterification, compounds such as 21-hydroxy-Sfl-pregnan-3,2O-dione-2'l-hemisuccinate can be obtained whichare active on the central nervous system. Furthermore, a series ofconventional reaction steps including the introduction of a 14,61 hydoxygroup, Reformatskij reaction of the 20-keto group and lactonizationfurnishes the known digitoxigenin acetate.

To prepare the compounds of Formula 1, several alternative processes canbe used, to wit:

(1) a 3-hydroxy-steroid of Formula II CH R4 wherein R to R, have theabove-indicated meanings, or a derivative of such a 3-hydroxy-steroidreactively esterified in the 3-position, can be reacted with an alcoholof the formula R OH or with a reactive derivative of such an alcohol;

a compound of the general Formula III (llHgR CO I -orar RiO g I R R, 3

R to R have the above-indicated meanings, and can be reacted with zincin aqueous acetic acid to remove the 17oc-OH group;

(3) a functionally modified 20-ketoand/or 21-R group in a steroidotherwise corresponding to Formula I can be liberated by solvolysis,preferably by acidic or alkaline hydroylsis, or by hydrogenolysis;

(4) a free hydroxy group can be esterified in the 21- position;

(5) an acidic or basic 21-ester can be converted into the ester saltthereof; and

(6) a double bond present in the 4(5)-position can be catalyticallyhydrogenated.

In Formulae I-III, the wavy lines in the 3- and 5- positions mean thatthe substituents in these positions can be Ot-POSltlOIlGd or,B-positioned. Accordingly, the formulae encompass the corresponding 5a:and 55-H- pregnanes and 4-pregnenes.

(III) wherein DETAILED DISCUSSION OF THE INVENTION In the formulae, Rrepresents alkyl groups advantageously of 1-10, preferably 1-4 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andfurthermore also sec.-butyl, tert.-butyl, n-amyl, isoamyl, nhexyl,n-octyl, and n-decyl; or cycloalkyl groups of especially 3-7, preferably5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

R represents a free or esterified hydroxy group. In the esters, the acidresidues are those derived from saturated or unsaturated aliphatic orcycloaliphatic, aromatic or heterocyclic carboxylic acids ofrespectively l-18 carbon atoms in total, examples including, but notlimited to:

formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid,the valeric acids, such as n-valeric acid or trimethylacetic acid, thecaproic acids, such as B-trimethylpropionic acid or diethylacetic acid,the enanthic, caprylic, pelargonic, capric or undecylic acids, theundecylenic acids, the lauric, myristic, palmitic or stearic acids,oleic acid, cyclopropy1-, cyclobutyl-, cyclopentylandcyclohexyl-carboxylic acids, cyclopropyl-methylcarboxylic acid,cyclobutylmethylcarboxylic acid, cyclopentylethylcarboxylic acid,cyclohexylethylcarboxylic acid, the cyclopentyl-, cyclohexylorarylacetic acids or propionic acids, e.g. phenylacetic acid or3-phenylpropionic acid, benzoic acid, phenoxyalkanoic acids, such asphenoxyacetic acid, as well as halocarboxylic acids, such aschloroacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyaceticacid, ether acids, such as 4-tert.-butylphenoxyacetic acid,3-phenoxypropionic acid, 4-phenoxybutyric acid, heterocyclic acids, suchas furan-Z-carboxylic acid, 5-tert.-butylfuran-2-carboxylic acid,S-bromofuran-Z-carboxylic acid, nicotinic acid or isonicotinic acid,fi-ketocarboxylic acids, e.g. acetoacetic acid, propionylacetic acid,butyrylacetic acid or capronoylacetic acid, or amino acids, such asdiethylaminoacetic acid or aspartic acid.

In place of the carboxylic acid residues, residues of sulfonic,phosphoric, sulfuric or hydrohalic acids can also be used.

Of particular importance are those esters containing a group whichimparts water-solubility to the compound, such as a hydroxyl, carboxylor amino group, since they can be employed for the preparation ofaqueous solutions. Such esters are derived from dicarboxylic acids ofpreferably 2-10 carbon atoms, examples of such acids including, but notlimited to: oxalic, succinic, maleic, glutaric, dimethylglutaric,pimelic, acetonedicarboxylic, acetylenedicarboxylic, phthalic,tetrahydrophthalic, hexahydrophthalic, endomethylenetetrahydrophthalic,endomethylenehexahydrophthalic, endoxyhexahydrophthalic orendoxytetrahydrophthalic acid, camphoric acid, cyclopropanedicarboxylicacid, cyclobutanedicarboxylic acid, diglycolic acid, ethylenebisglycolicacid, polyethylenebisglycolic acids, thioglycolic acid, furan-,dihydrofuranand tetrahydrofuran-dicarboxylic acids, quinolinic acid(2,3- pyridinedicarboxylic acid), cinchomeronic acid(3,4-pyridinedicarboxylic acid), the polyethyleneglycol-monoalkylethermono-esters of the above dicarboxylic acids. Additional acids includeamino-, alkylaminoor dialkylaminocarboxylic acids, and polybasicinorganic acids, such as sulfuric or phosphoric acids. By using theseacids, the corresponding esters can be produced, including, but notlimited to, for example: oxalates, succinates, maleates or the acidaddition salts of aminocarboxylic acid esters, e.g. the esters ofaspartic acid or diethylaminoacetic acid.

Typical ester salts of the acidic 21-esters, e.g. the sulfuric andphosphoric acid esters and the 2l-mono-esters of dibasic carboxylicacids are, in particular, the alkali salts, preferably the salts ofalkali metals, particularly the sodium salts; the ammonium salts; andthe ethanolammonium, diethanolamrnonium and triethanolammonium salts.Characteristic ester salts of the basic 21-esters are the acid additionsalts, especially the hydrohalogenides, e.g. the hydrochlorides andhydrobromides of 21-(aminocarboxylic acid)-esters.

With respect to the preparation of the final compounds of Formula I,starting compounds of Formula II are, in particular, those wherein theoptionally esterified hydroxy group in the 3-position is more reactivethan the hydroxy or ester group in the 21-position. Examples of suitablestarting compounds include, but are not limited to: 3ocand3fl-chloro-2l-hydroxy-5aand Sfl-pregnan-ZO- one, 311- and3p-bromo-21-hydroXy-5otand Sflregnan- 20-one and the corresponding3-sulfonic acid esters, e.g. the 3-methancsulfonates,3-benzenesulfonates and 3-ptoluenesulfonates of 30;,21- and of35,21-dihydroxy-5aand 5fl-pregnan-20-one, and the derivatives of thesecompounds which are not reactively esterified in the 21-position, forexample, the 21-acylates pertaining thereto, especially the Zl-acetates,e.g. 3a,21- and 3,8,21-dihydroxy- 5aand Sfi-pregnan-ZO-one-Zl-acetateand also the 4(5)- dehydro-derivatives of the above-mentioned compounds,such as 3aand 3fl-chloro-Z1-hydroxy-4-pregnen-20-one or 30:,21- or 38,2l-dihydroxy-4-pregnen-20-one-2 l-acetate.

Alcohols of the formula R OH suitable for the etherification arepreferably methanol and ethanol, but, of course, all other species of ROH can also be used, e.g. propanol, isopropanol, butanol, isobutanol,cyclopropan01, cyclobutanol, cyclopentanol, cyclohexanol andcycloheptanol. Reactive derivatives of these alcohols are thecorresponding chlorides, bromide, iodides, sulfates and sulfonic acidesters, particularly the esters of methanesulfonic, benzenesulfonic andp-toluenesulfonic acid, such as, e.g. methyl chloride, methyl bromideand methyl iodide, dimethyl sulfate, methylmethanesulfonate,-benzenesulfonate and -p-toluenesulfonate. Reactive derivatives alongthe lines of the present invention are also the correspondingdiazoalkanes, e.g. diazomethane and diazoethane.

The compounds of Formulae II and R OH (or the reactive derivativesthereof) are reacted in accordance with methods known from theliterature and dependent on the nature of the corresponding startingmaterials. Thus, it is possible, for example, to employ in the reactionone of the two reactants in the form of a reactive ester (halogenide orsulfonic acid ester), and the other in the form of the free alcohol orof an alcoholate, e.g. of the associated sodium or potassium alcoholate.Thus, for producing a 3-methoxy compound, it is possible, for example,to react a 3-chloroor 3-bromo-steroid or the 3-sulfonic acid ester of a3-hydroxy-steroid of Formula II with methanol and catalytic amounts ofan acid, e.g. p-toluenesulfonic acid, or instead with sodium methylate.However, the sodium compound of a S-hydroxy-steroid of Formula II canalso be made to react with methyl iodide, methyl bromide or with themethyl ester of a sulfonic acid.

Insofar as the solvent employed in the above method is not an excess ofthe etherification agent, for example, the alcohol R OH (such asmethanol or ethanol), the re action is normally conducted in thepresence of an additional inert solvent, suitable solvents in thisconnection being, for instance, hydrocarbons, such as hexane, benzene,toluene; or ethers, such as diethyl ether, diisopropyl ether,tetrahydrofuran or dioxane. The reaction is conducted at temperaturespreferably between C. and the boiling point of the solvent employed. Thereaction times range generally between 1 and 48 hours.

Another method resides in reacting a compound of Formula II containing afree 3-hydroxy-group with a diazoalkane, such as diazomethane, in thepresence of a Lewis acid, such as aluminum chloride or borontrifluoride. Suitable solvent are especially ethers, such as the onesenumerated above.

In a further method, it is possible to react the two components II and ROH in the form of the free alcohols in the presence of a strong acid,such as hydrogen chloride or sulfuric acid, and optionally in thepresence of an inert solvent.

The starting compounds of Formula II are obtainable, for example, byreducing the 3-keto-group of the desoxycorticosterone (optionally afterfirst etherifying or esterifying the 2l-hydroxy-group and/or blockingthe -ketogroup) selectively to a mixture of the 3aand 3B-hydroxycompounds, with the aid of a suitable reducing agent, such aslithium-tri-tert.-butoxyaluminum hydride or sodium borohydride. Theresulting mixture is separated, if desired (for example, bychromatography), and any protective groups present can then be cleaved,for example, by alkaline or acidic hydrolysis. The mixture (or theindividual epimers) can be converted with thionyl chloride or phosphoruspentachloride into the 3m and BB-chloro-compounds; with phosphoruspentabromide or triphenylphosphine dibromide into the 304- and3,8bromo-compounds; or with the corresponding sulfonic acid chloridesinto the B-methanesulfonates, 3-benzenesulfonates and3-p-toluenesulfonates.

The corresponding derivatives saturated in the 4-position are obtainableby catalytic heydrogenation of the unsaturated starting compounds or theintermediate products thereof. The hydrogenated intermediates can thenbe converted into the above-mentioned saturated starting materials inanalogous reaction sequences.

The starting substances of the saturated series can also be produced byselectively reducing pregnane-3,20-dione into a mixture of cand3B-hydroxypregnan-ZO-one, acetoxylating this mixture in the 2-position,and optionally halogenating same in the 3-position, as described above,or reacting same with a sulfonic acid chloride, as likewise set forth inthe foregoing.

The compounds of Formula I can also be produced by reductively removingthe 17u-hydroxy-group in steroids of Formula III, by treating the latterwith zinc in aqueous acetic acid. Preferably, a large excess of zincdust is employed, and the reaction mixture is heated for /2 to 4 hoursin boiling 50% acetic acid. Suitable starting materials are, forexample, 3ocand 3,B-methoxy-, -ethoxy-, -propoxy-, -cyclopentyloxyandcyclohexyloxyl7a, 21- dihydroxy-4-pregnen-20-one, as well as thecorresponding 6 5aand SB-pregnane derivatives saturated in the 4(5)-position. These starting compounds can be produced from cortexolone(Reichstein substance S), the dismethylenedioxy derivative of which isreduced with a complex metal hydride, e.g. sodium borohydride, to amixture of the epimeric 3-hydroxy compounds. After the protective grouphas been split oif, for example, by the effect of formic acid orhydrofluoric acid, an etherification in the 3-position is conducted. Aseparation of the 3-epimers and/or, if desired a hydrogenation of the4(5)-double bond, can be conducted at various stages.

Another process for obtaining the products of Formula I comprisesconverting a functionally modified ZO-ketogroup in a steroid otherwisecorresponding to Formula I into a free 20-keto-group by solvolysis,preferably by acidic or alkaline hydrolysis.

The functionally modified 20-keto-group is preferably present as theethylene ketal or the semicarbazone. Additional suitable functionalderivatives are other ketals, e.g. the dimethyl, diethyl, and propyleneketals, as well as hemithioketals (ethylene-, propylene-, dimethylanddiethylhemithioketals), thioketals (ethylene, pr0pylene-, dimethylanddiethylthioketals), enol ethers, thioenol ethers, cyanohydrins, oximes,phenylhydrazones and Girard derivatives (for example, the Girard-Tderivative).

The solvolysis of the above-mentioned 20 keto-deriva tives is conductedin the conventional manner described in the literature. The ketals arepreferably split by treatment with dilute acids. Suitable acids are, forexample, hydrochloric acid, sulfuric acid, perchloric acid, phosphoricacid, p-toluenesulfonic acid, oxalic acid, acetic acid, as Well as Lewisacids, such as boron trifluoride etherate. Ordinarily, an inert solventis employed, such as methanol, ethanol, acetone, dioxane, ether,tetrahydrofuran, benzene, chloroform or methylene chloride or mixturesof these solvents, optionally with the addition of water. Acetic acidcan simultaneously serve as the reactant and the solvent. The splittingtakes place readily at room temperature, but it is also possible toconduct the process at temperatures up to the boiling point of thesolvent employed, if splitting of the ether group in the 3-position isavoided, which latter measure does not entail any difficulties.Depending on the conditions employed, the reaction is terminated after afew minutes up to after 24 hours.

Thioketals and thioenol ethers are suitably split by treatment withmercury chloride/cadmium carbonate at room temperature or under heating,preferably in aqueous acetone, but also by hydrolysis with dilutehydrochloric acid or sulfuric acid. Hemithioketals are split byemploying the same acids, with mercury chloride or with Raney nickel,e.g. in acetic acid in the presence of sodium acetate. Alsosemicarbazones, oximes, phenylhydrazones and Girards T derivatives canbe split in an acidic medium, but the cyanohydrin is split with bases,such as methanolic potassium methylate or pyridine.

It is also possible to conduct the splitting operation in the presenceof a carbonyl compound, which, in turn, reacts with the liberatedreactant With the formation of the corresponding derivative. Thus, thesemicarbazone is converted into the free keto compound in a particularlyadvantageous manner by treatment with pyruvic acid. This reaction isconducted, for example, in aqueous dioxane or aqueous acetic acid atroom temperature or, more suitably, at elevated temperatures up to theboiling point of the solvent.

The ZO-keto-derivatives to be employed as the starting materials can beobtained, for instance, from desoxycorticosterone, the latter beingfirst partially functionalized in the 20-position, e.g. ketalized. Thethus-obtained derivative is thereafter reduced in the 3-position,optionally after first separating the isomers and by-products; thereduction process is preferably conducted with a complex metal hydride,such as lithium aluminum hydride or sodium borohydride. Saturatedstarting. substances are produced by catalytically hydrogenating the4(5)-double bond.

It is also possible, under solvolysis conditions, to simultaneouslyliberate the functionalized keto-group in the -position and accomplishthe etherification in the 3-position; this is done, for example, bytreating the ethylene ketal of 3,8,21-dihydroxy-4-pregnen-20-one withp-toluenesulfonic acid and R OH; the alcohol R OH serves at the sametime as the solvent and as the etherification agent.

The ethers of the general Formula I can also be obtained by converting afunctionally modified 2'1-R -group in a steroid otherwise correspondingto Formula I into an R -group by solvolysis. Thus, 21-hydroxy-steroidsof Formula I can be liberated from the 21-esters or 21-ethers thereof.Characteristic starting steroids are those wherein the 21-hydroxy-groupis present in the form of a readily splittable ester, for example, asthe acetate or benzoate, or a readily splittable ether. In thelast-mentioned case, the 21-ether-group must be more easily splittablethan the ether group in the 3-position. 21-ethers suitable for thispurpose are the benzyl, diphenylmethyl (benzhydryl), triphenylmethyl andtetrahydropyranyl ethers. Accordingly, suitable starting substances arethe following, for example: 3a and 3fi-methoxy-2l-acetoxy-5otand -55-pregnan-ZO-one, 3aand 3B-methoxy-2l-benzoyloxy-5aand-5,8-pregnan-20-one, 3aand -methoxy-21-benzyloxy-5aandSfl-pregnan-ZO-one, 341- and 3,8-methoxy-2ltriphenylmethoxy-5uand-5fl-pregnan-20-one, as well as the corresponding4(5)-dehydro-derivatives, e.g. 30:- and3fi-methoxy-21-acetoxy-4-pregnen-20-one and the analogous 3-ethoxy,3-propoxy, 3-isopropoxy, 3-butoxy, 3-cyclopentyloxy and 3-cyclohexyloxycompounds.

The Ill-esters are preferably converted into the free 21-hydroxy-compounds by alkaline or also by acidic hydrolysis. Thus, it ispossible, for example, to react these compounds with sodium or potassiumhydroxide, sodium or potassium carbonate, sodium or potassiumbicarbonate; in this connection, suitable solvents are lower alcohols,such as methanol, ethanol, or isopropanol, or mixtures thereof withwater.

The saponification is generally conducted at temperatures between roomtemperature and the boiling point of the solvent, the reaction timesranging between 1 and 48 hours. An acidic saponification of the21-ester-group can be accomplished with the aid of mineral acids, suchas hydrochloric or sulfuric acid; however, owing to the vulnerability ofthe ether group in the 3-position, alkaline saponification is preferred.

The splitting of the 21-ester-groups is preferably conducted in anacidic medium; in this connection, the conditions must be selected sothat the ether group in the 3- position is not affected. When employingreadily splittable 21-ethers, this is normally possible withoutdifiiculties. Of particular suitability are the triphenylmethyl (trityl)ether, tetrahydropyranyl ether, tert.-butyl ether and methoxymethylether, which are split in an organic solvent with the addition of amineral acid. Thus, it is possible, for example, to split the 2'1-tritylether of a steroid in chloroform saturated with hydrogen chloride, orthe 21- methoxymethyl ether in 50% aqueous acetic acid with 0.5%sulfuric acid added thereto, into the 21-hydroxycompounds.

21-ethers, such as 21-benzyl ether, 21-benzhydryl ether and 21-tritylether can also be split by catalytic hydrogenation. Suitable catalystsare, for example, noble metal, nickel and cobalt catalysts. The noblemetal catalysts can be employed in the form of supported catalysts, suchas, for example, palladium on charcoal, calcium carbonate or strontiumcarbonate; as oxide catalysts, such as platinum oxide, for instance; oras finely divided metal catalysts. Nickel and cobalt catalysts aresuitably employed as Raney metals, and nickel is also used supported onkieselguhr or pumice; palladium (5-10%) on charcoal is preferred. Thehydrogenation can be conducted at room temperature and under normalpressure, or also at elevated temperature and/ or under elevatedpressure. Preferably, the process is conducted at pressures between 1and 100 atmospheres and at temperatures between and +150 C. Suitably,the reaction is carried out in the presence of a solvent, e.g. methanol,ethanol, isopropanol, tert.-butanol, dioxane, glacial acetic acid,tetrahydrofuran or Water, the preferred solvent being ethyl acetate. Insome cases, the addition of catalytic amounts of a mineral acid isadvisable, for example, hydrochloric or sulfuric acid.

As still another process, 21-halosteroids which otherwise correspond toFormula I can be converted into the corresponding 2l-acylates byreaction with an alkali salt of a fatty acid. Thus, the acetoxycompounds corresponding to Formula I can be obtained, for example, bytreating the 21-bromides with anhydrous potassium acetate in acetone.The reaction requires temperatures ranging preferably from roomtemperature to the boiling point of the solvent and is terminated after1 to 48 hours.

It is also possible to employ starting compounds simultaneouslycontaining a functionally modified 20-ketogroup and a functionallymodified 21-R -group, insofar as both protective groups can be split offunder the same reaction conditions. Thus, a derivative of a compound ofFormula I ketalized in the 20-position and etherified in the 21-positioncan be hydrolyzed under the acidic conditions set forth hereinabove,wherein simultaneously the keto-group in the 20-position and the hydroxygroup in the 21-position are liberated.

In the compounds of Formula I, a free 21-hydroxy group can beesterified, if desired. Suitable esterification agents are all thoseacids or the derivatives thereof suitable for esterification which yieldphysiologically compatible esters; for example, the above-listed acidsor the derivatives thereof suitable for esterification can be employedin this connection. As esterification agents, the halogenides andanhydrides of the above-mentioned acids can be employed, for example.For interesterification methods, the lower alkyl esters thereof aresuitable. The esterification is normally conducted in the presence of anorganic base, such as pyridine. Whereas the base can also serve as thesolvent, an additional inert solvent can also be employed. Theesterification is generally conducted at temperatures between roomtemperature and the boiling point of the solvent employed and lastsnormally between /2 and 12 hours.

In an interesterification, the 2l-hydroxy-steroid to be esterified isdissolved in an excess of another ester of that acid with which thesteroid is to be esterified (in order to produce 21-acetoxy-steroids,for example, in ethyl acetate); as the catalyst, a small amount of astrong base is utilized, such as sodium methylate or potassium tert.-butylate.

For the production of the sulfuric acid esters, the reaction ispreferably conducted with the aid of sulfamic acid. In this connection,the process is conducted by mixing a steroid of Formula I (R =OH) inequal parts with sulfamic acid; introducing the mixture at temperaturesbetween 100 and +110 C., preferably at G, into absolute pyridine; andheating the mixture for a rather long period of time (15 minutes up to 3days) to C. After the usual working-up operation has been conducted, thecorresponding sulfuric acid esters are obtained, which can be convertedinto the sodium salts with pyridine and 12% aqueous sodium hydroxidesolution.

A double bond in the 4(5)-position present in the compounds of Formula Ican be catalytically hydrogenated, if desired. The hydrogenation isconducted under the above-described conditions. In starting materialscontaining simultaneously a group which can be hydrogenolyzed in the21-position (eg. a benzyloxy or trityloxy group) and a 4(5)-double bond,it is possible to remove this group by hydrogenolysis and to hydrogenatethe double bond, at the same time.

Referring now to Formula I, the following subgeneric groups of compoundsare preferred, as well as the ester salts of the acidic or basic2l-esters thereof:

(A) Compounds wherein:

R and R have the previously indicated meanings;

R represents alkyl of 1-4 carbon atoms or cycloalkyl of 3-7 carbonatoms; and

R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acidof up to 11 carbon atoms, or a phosphoric or sulfuric acid residue;

(B) compounds wherein R and R have the previous ly indicated meanings,and

R and R represent hydrogen;

(C) compounds wherein R and K, have the previously indicated meanings,and

R and R together represent a double bond 4(5);

(D) compounds wherein:

R and R represent hydrogen, and

R and R have the same meanings as in subgeneric e p( (E) compoundswherein:

R and R represent a 4(5)-double bond, and

R and R have the same meanings as in subgenerlc group (F) compoundswherein:

R and R have the previously indicated meanings;

R, has the same meaning as in subgeneric group (A) and R is methyl orethyl;

(G) compounds wherein:

R and R have the previously indicated meanings; R represents methyl orethyl; and

R represents hydroxyl or acetoxy.

The novel compounds of this invention can be employed in mixture withconventional pharmaceutical excipients. Carrier substances can be suchorganic or inorganic substances suitable for parenteral, enteral, ortopical application, and which, of course, do not delete riously reactwith the novel compounds, such as, for example, water, vegetable oils,polyethylene glycols, benzyl alcohol, gelatin, lactose, amylose,magnesium stearate, talc, Vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions, as well as suspensions, emulsionsor implants. Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or drageeswhich are also characterized by talc and/or a carbohydrate carrier orbinder or the like, the cabohydrate carrier being preferably lactoseand/or corn starch and/ or potato starch. A syrup or the like can alsobe used wherein a sweetened vehicle is employed.

For topical application, viscous to semisolid forms are used such asliniments, salves or creames, which are, if desired, sterilized, ormixed With auxiliary agents, such as preservatives, stabilizers, orWetting agents, or salts for influencing the osmotic pressure, or withbuffer substances.

The substances of this invention are generally administered to animals,including, but not limited to, mammals and avians, e.g. cattle, cats,dogs, and poultry. A daily dosage of the compounds of Formula Icomprises about 0.1-100, preferably 1-10 mg. together with 1-5000 mg. ofpharmaceutically acceptable carriers and/or excipients. The dose can beadministered all at once or as divided dosages throughout the day. Ingeneral, the mg./ kg. ratio is preferably about 0.001 to 1 mg. to kg. ofbody weight.

Oral administration is preferred, the compounds of Formula I beingparticularly valuable in the treatment of patients who cannot toleratethe glucocorticoidal side efiects.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description,

10 utilize the present invention to its fullest extent. The followingpreferred specific embodiments are, therefore, to be construed as merelyillustrative and not limitative of the remainder of the specificationand claims in any Way whatsoever.

EXAMPLE 1 (a) 100 mg. of304,2l-dihydroxyl-pregnen-ZO-oneimono-p-toluenesulfonate is allowed tostand in 5 ml. of methanol in the presence of 10 mg. ofp-toluenesulfonic acid for 24 hours. Then, 5 ml. of water is added, thereaction mixture is extracted several times with ether, the etherextracts are Washed with water, dried over sodium sulfate, evaporated,and the residue is chromatographed in chloroform on silica gel.3or-m6thOXY-21-hYdfOXY-4- pregnen-ZO-one, M.P. 143-145" C. is obtained.

(b) 500 mg. of 3a-methoxy-2l-hydroxy-4-pregnen-20- one is dissolved in 3ml. of pyridine and mixed with 3 ml. of acetic anhydride. The reactionmixture is agitated at room temperature for 3 hours, poured into water,and then extracted with chloroform. The combined chloroform extracts arewashed neutral, dried over sodium sulfate and evaporated, thus obtaining3a:-methoxy-21-acetoxy-4- pregnen-ZO-one.

The starting material is obtained by selective reduction of the3-keto-group of desoxycorticosterone with sodium borohyride inisopropanol; separation of the thus-obtained 304- andS/E-hydroxy-steroids by chromatography; and reaction of the 3a-isomerwith p-toluenesulfonyl chloride/ pyridine.

EXAMPLE 2 100 mg. of Son-methoxy-17a,2l-dihydroxyl-pregnen- 20 one isdissolved in 5 ml. of acetic acid, mixed with 5 ml. of water and 1 g. ofzinc dust and refluxed for minutes. The mixture is filtered, and theZinc is washed with methanol. The filtrate is mixed with ice, almostneutralized with 3 N sodium hydroxide solution and extracted severaltimes with ether. The ether extracts are washed with water, dried oversodium sulfate, evaporated, and the thus-obtained crude product ispurified by chromatographing same in chloroform on silica gel. 30:-methoxy-Zl-hydroxy-4-pregnen-20-one, M.P. l43145 C., is produced.

The starting material is obtained by converting Cor texolon into thebismethylenedioxy derivative (M.P. 255257 C.), reduction with lithiumaluminum hydride to produce the 3-hydroxy-compound, M.P. 153155 C.,removing the bismethylenedioxy group by hydrolysis, tosylation in the3-position, methanolysis and chromatographic separation of thethus-obtained 3aand 3,8-1nethoxy-epimers.

EXAMPLE 3 (a) 2.6 g. of 20,20-ethylenedioxy-4-pregnene-3[3,21-diol isdissolved, together with 230 mg. of p-toluenesulfonic acid, in 1.3 l. ofmethanol and allowed to stand at room temperature for 8 hours.Thereafter, the reaction solution is poured into 1.3 l. of Water,extracted several times with ether, the ether extracts washed withwater, dried over sodium sulfate and concentrated by evaporation. Theresidue (1.7 g.) is dissolved in 15 ml. of chloroform and separated bylayer chromatography on three plates coated with silica gel of a lengthof cm. There are obtained 3 B methoxy 21-hydroxy-4-pregnen-20-one, M .P.101-103 C. and 3a-methoxy-21--hydroxy-4-pregnen-20- one, M.P. 143l45 C.

The starting material is produced as follows:

30 g. of desoxycorticosterone is ketalized in the conventional mannerwith ethylene glycol in the presence of p-toluenesulfonic acid inboiling benzene (6 hours), thus obtaining a mixture ofdesoxycorticosterone with the three possible ketals. \By separation bymeans of layer chromatography in chloroform on silica gel, 7 g. of aresinous 20,20-ethylenedioxy-2l-hydroxy 4 pregnen-3- one is isolated.

This substance is dissolved in a mixture of 200 m1. of absolutetetrahydrofuran, as well as 200 ml. of absolute ether, and is stirredduring the course of 20 minutes under ice cooling and a purge stream ofnitrogen into a suspension of 4 g. of lithium aluminum hydride in 1 l.of absolute ether. After another two hours of agitation at roomtemperature, the reaction mixture is decomposed in the customary mannerfirst with ethyl acetate and then With water, and worked up. Thethus-obtained crude product is recrystallized from methanol and yields20,20- ethylenedioxy-4-pregnene-35,2l-diol, M.P. 208-210 C.

(b) 0.37 g. of 3B-methoxy-Z1-hydroxy-4-pregnen-20- one is hydrogenatedin ml. of ethyl acetate of .50 mg. of platinum dioxide at roomtemperature until 1 molar equivalent of hydrogen has been absorbed. Thereaction mixture is filtered off, the filtrate is concentrated byevaporation, and a mixture of 3,8 methoxy-21-hydroxy-5apregnan--one and3B-methoxy-2l-hydroxy-SB-pregnan- 20-one is obtained, which is separatedby chromatography on silica gel.

EXAMPLE 4 (a) 300 mg. of the 21-trityl ether of 3[5'-methoxy-21-hydroxy-4-pregnen-20-one is dissolved in ml. of 95% acetic acid and 10ml. of glacial acetic acid and allowed to stand at 30 C. for 7 hours.The acetic acid is removed under reduced pressure and replaced bybenzene. The solution is chromatographed on silica gel in order toremove the concomitantly produced triphenylcarbinol. By elution withchloroform and subsequent concentration, 3,B-methoxy-Z1-hydroxy-4-pregnen-ZO-one, M.P. l01-103 C., is obtained.

The starting material is produced as follows:

10 g. of desoxycorticosterone is converted into the 21- trityl-ether byreaction with trityl chloride in pyridine (yield: 6.7 g., M.P. 157-160"C.).

6 g. of the trityl ether is partially reduced in the 3- position withlithium-tri-tert.-butoxyaluminum hydride. The oily crude product (5.5g.) is subjected to solvolysis in methanol in the presence ofpatoluenesulfonic acid, thus obtaining a mixture of 3B- and3ot-methoxy-2l-hydroxy- 4-pregnen-20one-2l-trityl ether, which mixtureis separated by plate chromatography. The 21-trityl ether of3,8-methoxy-21-hydroxy-4-pregnen-20-one is obtained in the form of ayellowish oil.

(b) 2.28 g. of 3,!3-methoxy-21-hydroxy-4-pregnen-20- one and 2.28 g. ofsulfamic acid are dissolved in 17 m1. of pyridine and agitated on asteam bath under the exclusion of moisture for 1.5 hours. After cooling,the reaction mixture is vacuum-filtered, and the residue is extractedwith ml. of pyridine. The filtrate and the Washing liquid are shaken outwith ether, and the pyridine phase is subsequently concentrated. Theresidue is taken up in 20 ml. of pyridine and 27 ml. of 12% sodiumhydroxide solution, agitated for 10 minutes and then again extractedwith ether. The combined ether phases are dried over sodium sulfate andevaporated, thus obtaining the sodium salt of3,8-methoxy-21-hydroxy-4-pregnen20-one- 21-sulfate.

(c) A solution of 0.34 g. of 3fl-methoxy-21-hydroxy- 4-pregnen-20-one in8 ml. of dioxane is mixed with 0.1 ml. of absolute pyridine and 0.1 ml.of chloroacetyl chloride. The reaction mixture is allowed to stand for 3days at room temperature, poured into Water, and 0.33 g. of crude3fi-methoxy-21-chloroacetoxy-4-pregnen-20 one is thus obtained; thelast-mentioned compound is boiled for 1 hour with 3.3 g. of diethylaminein 25 ml. of acetone and 2 ml. of water and is then evaporated. Theresidue is taken up in 20 ml. of chloroform, the mixture is shaken withsodium bicarbonate solution and with water, dried, evaporated, and3fl-rnethoxy-21-diethylaminoacetoxy-4- pregnen-ZO-one is obtained.

EXAMPLE 5 250 mg. of 35,21-dihydroxy-4-pregnen-20-one is dissolved in130 ml. of methanol and allowed to stand at room temperature for 10hours with 23 mg. of p-toluenesulfonic acid. The reaction mixture ispoured into 200 ml. of Water, extracted with ether, the ether solutionWashed with water, dried over sodium sulfate and evaporated. A mixtureof 3,8-methoxy-21hydroxy-4-pregnen-20-one and 3ot-methoxy-21-hydroxy 4pregnen-ZO-one is obtained Which is separated by chromatography asdescribed in Example 3.

The starting material is produced from20,20-ethylenedioxy-4pregnene3fi,2l-diol with 20% aqueous-ethanolicoxalic acid solution.

EXAMPLE 6 575 mg. of 35 methoxy 21 triphenylmethOXy-Sapregnan-ZO-one isdissolved in 60 ml. of ethyl acetate and hydrogenated at roomtemperature after the addition of 350 mg. of 5% palladium-charcoal. Thecatalyst is fi1 tered off, and the filtrate is evaporated, thusobtaining 3B-methoxy-21-hydroxy-5a-pregnan-20-one.

In order to produce the starting material, 21-hydroxy- 50cpregnane-3,20-dione is converted into the 2l-tritylether and selectivelyreduced in the 3-position with tritert.-butoxylithiumaluminum hydride to3 ,8 hydroxy-2ltrityloxy-5a-pregnan 20 one; etherification withmethanol/p-toluenesulfonic acid results in3,8-methoxy-21-trityloxy-5ot-pregnan-20-one.

EXAMPLE 7 388 mg. of 2l-acetoxy-35-methoxy-4-pregnen-20-one is dissolvedin 12 ml. of methanol, mixed with a solution of 93 mg. of sodiumbicarbonate in 2 ml. of water and boiled for 10 minutes. The mixture ispoured into ml. of water and extracted with chloroform. The combinedchloroform extracts are dried over sodium sulfate and evaporated; thethus-obtained 3,8-methoxy-2l-hydroxy-4-pregnen-20-one is recrystallizedfrom methanol, M.P. 101 103 C.

In order to prepare the starting material, the 2l-acetate ofll-desoxycorticosterone is ketalized selectively in the 20-position withethylene glycol; the ZO-ketal is reduced in the 3-position with sodiumborohydride in methanol, and the thus-produced21-acetoxy-20,20-ethylenedioxy- 4-pregnen-3fl-ol is simultaneouslydeketalized in the 20-positi0n and etherified in the 3-position withmethanol/ p-toluenesulfonic acid. The mixture of 3u-methoxy-21-acetoxy-4-pregnen-20-one and 3,8-methoxy-21-acetoxy-4- pregnen-20-oneobtained in this manner is separated by chromatography.

EXAMPLE 8 Analogously to Example 3, the following compounds are producedby splitting the corresponding 20,20-ethylenedioxy-compounds:

3vt-methoxy-21-hydroxy-5a-pregnan-20-one 3ot-methoxy-2l-hydroxy-5,B-pregnan-20-one3,8-methoxy-21-hydroxy-5a-pregnan-20-one3fi-methoxy-21-hydroxy-5,8-pregnan-20-one3a-eth0Xy-21-hydroxy-5a-pregnan-20-one3ot-ethoxy-21-hydroxy-5/i-pregnan-20-one3,8-ethoxy-21-hydroxy-5a-pregnan-ZO-One3B-ethoxy-21-hydroxy-SB-pregnan-ZO-one3a-ethoxy-Zl-hydroxy-4-pregnen-20-one3B-ethoxy-21-hydroxy-4-pregnen-20=one3a-propoxy-21hydroxy-5a-pregnan-20-one 3oc-p1'OpOXY-21-hYdrOXY-5,B-pregnan-ZO-one 3,8-propoxy-21-hydroxy-5u-pregnan-ZO-One3B-propoxy-21-hydroxy-5/3-pregnan-20-one3ot-propoxy-21-hydroxy-4-pregnen-20-one 3p-propoxy-21-hydroxy-4-pregnen-20-one3a-cyclopentyloxy-2l-hydroxy-Sa-pregnan-ZO-One 3a-cyclopentyloxy-21-hydroxy-5p-pregnan-20-one 3fi-cyclopentyloxy-Z1-hydroxy-5ot-pregnan-20-one 3 p-cyclopentyloxy-2l-hydroxy-5 8-pregnan-20-one3ot-cyclopentyloxy-21-hydroxy-4-pregnen-20-one 3fi-cyclopentyloxy-Z1-hydroxy-4-pregnen-20-one 133a-cyclohexyloxy-2I-hydrOXy-Sa-pregnan-20-one3ot-cyclohexyloxy-21-hydroxy-Sfi-pregnanQO-one3/8-cyclohexyloxy-21-hydroxy-5a-pregnan-ZOone3/8-cyclohexyloxy-21-hydroxy-5 3-pregnan-20-one3u-cyclohexyloxy-21-hydroxy-4-pregnen-20-one3/3-cyclohexyloxy-21-hydroxy-4-pregnen-20-one.

The following examples include pharmaceutical com positions of the novelcompounds:

EXAMPLE A: Tablets Each tablet contains:

3a-methoxy-21-hydroxy-4-pregnen-20-one '2 Lactose 70 Wheat starch 18Talc 10 EXAMPLE B: Coated tablets Each tablet contains:

3u-methoxy-21-hydroxy-4-pregnen-20-one 3 Lactose 80 Potato starch 15Magnesium stearate 2 The coating (150 mg.) is a conventional mixture ofcorn starch, sugar, talc, and tragacanth.

EXAMPLE C: Solution for injection A solution of 2 g. of3a-methoxy-21-hydroxy-4-pregnen- 20-one in 998 ml. of sesame oil isprepared and filled into ampoules in such a manner that each ampoulecontains 2 mg. of said sodium salt.

Instead of 3a methoxy-Zl-hydroxy-4-pregnen-20-one, other compoundscovered by Formula I can be incorporated into similar compositions.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

1. A member selected from the group consisting of a compound of thefollowing formula, physiologically acl4 ceptable salt of an acidic21-ester thereof and a physiologically acceptable salt of a basic21-ester thereof:

OH R;

wherein R is lower alkyl or cycloalkyl of 3-7 carbon atoms;

R and R each represent hydrogen or together a double bond; and

R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acidof up to 11 carbon atoms, or a phosphoric or sulfuric acid residue.

2. A member as defined by claim 1 wherein R and R have the previouslyindicated meanings, and

R and R represent hydrogen.

3. A member as defined in claim 1 wherein R and R have the previouslyindicated meanings, and

R and R together represent a double bond 4(5).

4. A member as defined by claim 1 wherein R R and R have the previouslyindicated meanings;

R is methyl or ethyl.

5. A member as defined by claim 1 wherein R and R have the previouslyindicated meanings;

R represents methyl or ethyl; and

R represents hydroXyl or acetoxy.

6. A member as defined in claim 1 wherein said member is3a-methoxy-21-hydroxy-4-pregnene-20-one.

7. A member as defined by claim 1 wherein said member is3fi-methoXy-2l-hydroxy-4-pregnene-20-one.

No references cited.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 597,453 Dated August 3, 1971 Inventor(s) Klaus Irmscher et a1 It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the Claims:

Claim 1, in the formula, line 2, "CH" should be --CO---.

Signed and sealed this 27th day of June 1972.

(SEAL) Attest ROBERT GOTTSCHALK EDHARD M.FLETGHER,JR. Attestinp; OfficerCommissioner of Patents LISCOMM-DC BOS'IG PGD FORM PD-IOSO (10-69) hu,s. sovrmmrm' nmmns OFFICE: 190 o-au-an

